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Overview of the Prevention and Management of CINV
James J. Natale, PharmD, BCOP
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Overview of the Prevention and Management of CINV

James J. Natale, PharmD, BCOP
The prevention of chemotherapy-induced nausea and vomiting (CINV) is critically important in reducing morbidity and total healthcare costs in patients receiving emetogenic chemotherapy. The different types of CINV (ie, acute, delayed, anticipatory, breakthrough, and refractory) are controlled through various pathways and neurotransmitters, so the pharmacologic approach to prevention and treatment varies based on the type of CINV. New therapeutic agents and combinations of agents have changed the dynamic of CINV control, and national guidelines have been recently updated based on current evidence. Along with current national guideline recommendations, this educational activity will provide an overview of the pathophysiology of CINV and how the mechanisms of action of various antiemetic agents relate to efficacy and safety in the prevention and treatment of CINV.
Am J Manag Care. 2018;24:-S0
Despite substantial improvements in cancer treatment and supportive care over the past 4 decades, chemotherapy-induced nausea and vomiting (CINV) remains one of the most distressing and debilitating adverse effects (AEs) of chemotherapy. When left untreated, CINV may affect between 60% and 80% of patients with cancer1 and be associated with premature discontinuation of treatment, diminished quality of life, complications such as dehydration and electrolyte imbalances,2 and ultimately decreased treatment success and increased cost of care.3 Thus, the prevention of CINV is critically important in reducing morbidity and total healthcare costs, as well as increasing the quality of care in patients receiving highly and/or moderately emetogenic chemotherapy.

The pathogenesis of CINV involves multiple organ systems, central and peripheral pathways, and neurotransmitters. It is dependent on several factors, including the emetogenicity of the chemotherapy regimen, the dose and rate of administration of the chemotherapy agent(s), various environmental triggers (ie, smells, sites, or locations that are associated with past experiences of CINV), and patient-related factors.4 The process of CINV involves communication between the central nervous system and gastrointestinal (GI) tract; the targetable neurotransmitters and their associated receptors involved in CINV include serotonin (5-hydroxytryptamine [5-HT]) and serotonin receptors, substance P and the neurokinin-1 (NK1) receptor, and dopamine and dopamine receptors.5 There are a number of different 5-HT receptors, with the third type, 5-HT3 receptor, being the most important in the CINV process. The physiologic process of nausea and/or vomiting in response to chemotherapy administration involves the release of these neurotransmitters and activation of their associated receptor(s) in the chemoreceptor trigger zone, GI tract, and vomiting center located in the medulla.6

Five categories are used to classify CINV based on the pathways in which nausea and vomiting (NV) are produced: acute, delayed, anticipatory, breakthrough, and refractory.4 Acute CINV occurs within 24 hours of receiving chemotherapy and is triggered primarily by serotonin receptors in the GI tract.4 Delayed CINV occurs more than 24 hours after receiving chemotherapy and is mediated primarily by substance P.4 The actions of substance P are mediated primarily by NK1 receptors and is a major neurotransmitter in the central, peripheral, and enteric nervous systems that affects sensory and, most notably, nociceptive pathways and inflammation.7 The administration of certain chemotherapy agents, such as cisplatin, carboplatin, cyclophosphamide, and/or doxorubicin, is commonly associated with delayed CINV.8 Anticipatory CINV is generally considered a conditional response to chemotherapy due to previous poor experiences from chemotherapy.4 The incidence of anticipatory CINV ranges from 18% to 57% and is more common in younger patients.8 Breakthrough CINV occurs within 5 days of chemotherapy despite appropriate prophylaxis, and refractory CINV occurs in subsequent chemotherapy cycles after the occurrence of breakthrough CINV in prior cycles, excluding anticipatory CINV.4,9 Several modifiable and unmodifiable therapy-related and patient-related risk factors have been associated with CINV, as summarized in Table 1.4,10

Chemotherapy agents and combinations of agents are categorized as minimal, low, moderate (MEC), or high (HEC) emetogenic chemotherapy, and CINV prevention and treatment strategies are typically dictated by these categories.8 The moderate and high emetogenic chemotherapies (MEC and HEC, respectively) are shown in Table 2.8,11

Therapy for CINV

The different types of CINV are controlled through various pathways and neurotransmitters working in concert with each other, so the pharmacologic approach to prevention and treatment will need to involve the usage of agents that target each of these pathways and neurotransmitters to maximize outcomes. The agents used in the prevention and treatment of CINV, along with their mechanisms of action, are summarized below.

Dexamethasone

Dexamethasone is a corticosteroid commonly used in 2-, 3-, or 4-drug combinations with other agents.6 Per national guidelines, dexamethasone is recommended for first-line use in combination with other agents for the prevention of both acute and delayed CINV in patients receiving HEC and/or MEC.8,11 Healthcare providers should be aware of the AE profile that may challenge the benefits of this agent in some patients receiving HEC or MEC.12 A study by Vardy et al found tolerability issues reported by patients that were attributed to dexamethasone in the week following MEC, including insomnia (45%), indigestion/epigastric discomfort (27%), agitation (27%), increased appetite (19%), weight gain (16%), and acne (15%).12

Dexamethasone should not be used with most immunotherapies and cellular therapies concurrently, as it may reduce their efficacy. AEs, such as immunosuppression, that occur with long-term use should be carefully considered for each patient.8 Caution should be used in patients with diabetes because dexamethasone may increase serum glucose levels. Dexamethasone may cause dyspepsia, so use of an H2 antagonist or proton pump inhibitor may be necessary. Additionally, dosing dexamethasone in the morning, when feasible, may minimize insomnia.8

5-HT3 Receptor Antagonists

Because serotonin is the primary mediator of acute CINV, 5-HT3 receptor antagonists (5-HT3 RAs) play an integral role in its prevention. 5-HT3 RAs should be scheduled prior to HEC and/or MEC administration, as opposed to an as-needed basis.8 First-generation 5-HT3 RAs include ondansetron, dolasetron, granisetron, and tropisetron (not available in the United States).13 In clinical trials, 5-HT3 RAs have demonstrated excellent results in preventing acute CINV.9 In 2003, a second-generation 5-HT3 RA, palonosetron, was approved.14 Compared with first-generation agents, palonosetron has a prolonged plasma half-life (40 vs 3-9 hours), stronger binding affinity to the receptor (100 times stronger), and in vitro study results demonstrating specific interactions with receptors that are different from first-generation 5-HT3 RAs (allosteric binding and positive cooperative vs competitive binding).13 In a pooled analysis of phase 3 studies comparing palonosetron to ondansetron, dolasetron, and granisetron, authors found that complete response rates for CINV were significantly higher among patients given palonosetron compared with first-generation 5-HT3 RAs in the delayed and overall phases (delayed CINV: 57% vs 45%; P <.0001; overall CINV: 51% vs 40%; P <.0001).15 Rates of AEs were similar among all 5-HT3 RAs.15

Common AEs associated with both first- and second-generation 5-HT3 RAs are constipation, headache, and increased alanine aminotransferase (ALT).15 Although 5-HT3 RAs are recommended in first-line prevention of CINV, there have been concerns raised in the medical literature about cardiovascular AEs.16 Potential AEs include prolongation of the QT interval, which is associated with serious ventricular arrhythmias, and blockade of voltage-dependent sodium channels and potassium channels.16

A recent meta-analysis by Tricco et al evaluated the comparative safety and efficacy of 5-HT3 RAs alone or in combination with a steroid.16 The analysis included 299 studies (N = 58,412 patients), and no significant differences between 5-HT3 RAs were found regarding any reported harms, arrhythmia, and mortality. However, dolasetron with dexamethasone was associated with a greater risk of QT prolongation than ondansetron with dexamethasone.16 Because dexamethasone is typically used in combination with a 5-HT3 RA, healthcare providers should maintain awareness of the varying potential for QT prolongation, depending on which 5-HT3 RA, its dose, and route of administration used.

In efficacy outcomes, Tricco et al found that all agents were superior to placebo regarding prevention of NV and CINV. However, only ondansetron and ramosetron (the latter not commercially available in the United States) were superior to placebo in the treatment of severe vomiting.16 Overall, the authors found that palonosetron with a steroid to be the safest and most effective agent.16

NK1 Receptor Antagonists

The 2003 approval of aprepitant,17 followed by the 2008 approval of its intravenous (IV) drug, fosaprepitant,18 brought a new class of antiemetic therapy to market: NK1 receptor antagonists (NK1 RAs).19 These agents reduce the activity of substance P through blockage of NK1 receptors, which works primarily against delayed CINV, but also has been shown to help with acute CINV.20 The addition of an NK1 RA to 5-HT3 RA/dexamethasone has been shown to be more effective in preventing acute and delayed CINV in patients receiving HEC than 5-HT3 RA/dexamethasone alone.9 These agents are recommended alongside dexamethasone and 5-HT3 RAs as first-line therapy in the prevention of CINV for HEC and MEC, with additional risk factors, previous prevention/treatment failures, or therapies associated with greater emetogenic risk (ie, irinotecan or oxaliplatin).8 In recent years, 3 additional NK1 RAs have received approval for use in CINV: netupitant and fosnetupitant, both in a fixed combination with palonosetron (NEPA) (ie, the fixed combination of fosnetupitant/palonosetron IV and netupitant/palonosetron capsule), and rolapitant.17,21,22

Rolapitant demonstrated superior efficacy in the prevention of delayed CINV (>24-120 hours after MEC or HEC) over placebo in combination with a 5-HT3 RA and dexamethasone during phase 3 trials.23,24 In a phase 3 trial evaluating rolapitant in patients receiving MEC, AEs were similar between the treatment and control groups, with the most common being fatigue, constipation, and headache.24 AEs were also similar between groups in 2 phase 3 trials evaluating rolapitant in patients receiving HEC, and these events included neutropenia, anemia, and leukopenia.23

 
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